Method for mapping a heart using catheters having ultrasonic position sensors

ABSTRACT

A method for mapping a heart comprises the steps of inserting a mapping catheter having an ultrasonic position sensor into the heart. At least one reference catheter having an ultrasonic position sensor is also inserted into the heart. The position of the mapping catheter is determined relative to the at least one reference catheter and a portion of the heart is mapped with the mapping catheter. Additionally, the at least one reference catheter may be provided outside of the heart.

FIELD OF THE INVENTION

This is a Continuation of U.S. patent application Ser. No. 09/111,317,filed on Jul. 7, 1998, now issued U.S. Pat. No. 6,285,898, which is aContinuation-in-Part of U.S. patent application Ser. No. 08/595,365,filed on Feb. 1, 1996, now issued U.S. Pat. No. 5,738,096, which claimsthe benefit of U.S. Provisional Patent Application No. 60/009,769, filedon Jan. 11, 1996, and is a Continuation-in-Part of U.S. patentapplication Ser. No. 08/311,593, filed on Sep. 23, 1994, now issued U.S.Pat. No. 5,546,951, which is a Division of U.S. patent application Ser.No. 08/094,539, filed on Jul. 20, 1993, now issued U.S. Pat. No.5,391,199.

BACKGROUND OF THE INVENTION

Cardiovascular diseases accounted for approximately 43 percent of themortality in the United States of America in 1991 (923,000 persons).However, many of these deaths are not directly caused by an acutemyocardial infraction (AMI). Rather, many patients suffer a generaldecline in their cardiac output known as heart failure. Once the overtsigns of heart failure appear, half the patients die within five years.It is estimated that between two and three million Americans suffer fromheart failure and an estimated 200,000 new cases appear every year. Inmany cases heart failure is caused by damage accumulated in thepatient's heart, such as damage caused by disease, chronic and acuteischemia and especially (˜75%) as a result of hypertension.

A short discussion of the operation of a healthy heart is usefull inorder to appreciate the complexity of the functioning of the heart andthe multitude of pathologies which can cause heart failure. FIG. 1A is aschematic drawing of a cross-section of a healthy heart 20. In generalheart 20 comprises two independent pumps. One pump comprises a rightatrium 22 and a right ventricle 24 which pump venous blood from aninferior and a superior vena cava to a pair of lungs (not shown) to beoxygenated. Another pump comprises a left atrium 26 and a left ventricle28, which pump blood from pulmonary veins (not shown) to a plurality ofbody systems, including heart 20 itself. The two ventricles areseparated by a ventricular septum 30 and the two atria are separated byan atrial septum 32.

Heart 20 has a four phase operational cycle in which the two pumps areactivated synchronously. FIG. 1B shows a first phase, called systolic.During this phase, right ventricle 24 contracts and ejects blood througha pulmonic valve 34 to the lungs. At the same time, left ventricle 28contracts and ejects blood through an aortic valve 36 and into an aorta38. Right atrium 22 and left atrium 26 are relaxed at this point andthey begin filling with blood, however, this preliminary filling islimited by distortion of the atria which is caused by the contraction ofthe ventricles.

FIG. 1C shows a second phase, called rapid filling phase and indicatesthe start of a diastole. During this phase, right ventricle 24 relaxesand fills with blood flowing from right atrium 22 through a tricuspidvalve 40, which is open during this phase. Pulmonic valve 34 is closed,so that no blood leaves right ventricle 24 during this phase. Leftventricle 28 also relaxes and is filled with blood flowing from leftatrium 26 through a mitral valve 42, which is open. Aortic valve 36 isalso closed to prevent blood from leaving left ventricle 26 during thisphase. The filling of the two ventricles during this phase is affectedby an existing venous pressure. Right atrium 22 and left atrium 26 alsobegin filling during this phase. However, due to relaxation of theventricles, their pressure is lower than the pressure in the atria, sotricuspid valve 40 and mitral valve 42 stay open and blood flows fromthe atria into the ventricles.

FIG. 1D shows a third phase called diastatis, which indicates the middleof the diastole. During this phase, the ventricles fill very slowly. Theslowdown in filling rate is due to the equalization of pressure betweenthe venous pressure and the intra-cardiac pressure. In addition, thepressure gradient between the atria and the ventricles is also reduced.

FIG. 1E shows a fourth phase called atrial systole which indicates theend of the diastole and the start of the systole of the atria Duringthis phase, the atria contract and inject blood into the ventricles.Although there are no valves guarding the veins entering the atria,there are some mechanisms to prevent backflow during atrial systole. Inleft atrium 26, sleeves of atrial muscle extend for one or twocentimeters along the pulmonary veins and tend to exert a sphincter-likeeffect on the veins. In right atrium 22, a crescentic valve forms arudimentary valve called the eustachian valve which covers the inferiorvena cava. In addition, there may be muscular bands which surround thevena cava veins at their entrance to right atria 22.

FIG. 1F is graph showing the volume of left ventricle 24 as a functionof the cardiac cycle. FIG. 1F clearly shows the additional volume ofblood injected into the ventricles by the atria during atrial systole aswell as the variance of the heart volume during a normal cardiac cycle.FIG. 1G is a graph which shows the time derivative of FIG. 1F, i.e., theleft ventricle fill rate as a function of cardiac cycle. In FIG. 1G twopeak fill rates are shown, one in the beginning of diastole and theother during atrial systole.

An important timing consideration in the cardiac cycle is that theatrial systole must complete before the ventricular systole begins. Ifthere is an overlap between the atrial and ventricular systoles, theatria will have to force blood into the ventricle against a raisingpressure, which reduces the volume of injected blood. In somepathological and induced cases, described below, the atrial systole isnot synchronized to the ventricular systole, with the effect of a lowerthan optimal cardiac output.

It should be noted that even though the left and the right sides ofheart 20 operate in synchronization with each other, their phases do notexactly overlap. In general, right atrial systole starts slightly beforeleft atrial systole and left ventricular systole starts slightly beforeright ventricular systole. Moreover, the injection of blood from leftventricle 26 into aorta 38 usually begins slightly after the start ofinjection of blood from right ventricle 24 towards the lungs and endsslightly before end of injection of blood from right ventricle 24. Thisis caused by pressures differences between the pulmonary and bodycirculatory systems.

When heart 20 contracts (during systole), the ventricle does notcontract in a linear fashion, such as shortening of one dimension or ina radial fashion. Rather, the change in the shape of the ventricle isprogressive along its length and involves a twisting effect which tendsto squeeze out more blood. FIG. 2 shows an arrangement of a plurality ofmuscle fibers 44 around left ventricle 28 which enables this type ofcontraction. When muscle fibers 44 are arranged in a spiral manner asshown in FIG. 2 and the activation of muscle fibers 44 is started froman apex 46 of left ventricle 28, left ventricle 28 is progressivelyreduced in volume from the bottom up. The spiral arrangement of musclefibers 44 is important because muscle fibers typically contract no morethan 50% in length. A spiral arrangement results in a greater change ofleft ventricular volume than is possible with, for example, a flatarrangement in which the fibers are arranged in bands around the heart.An additional benefit of the spiral arrangement is a leverage effect. Ina flat arrangement, a contraction of 10% of a muscle fiber translatesinto a reduction of 10% of the ventricular radius. In a spiralarrangement with, for example, a spiral angle 48 of 45°, a 10%contraction translates into a 7.07% contraction in ventricular radiusand a 7.07% reduction in ventricular length, Since the ventricularradius is typically smaller than the ventricular length, the net resultis that, depending on spiral angle 48, a tradeoff is effected between agiven amount of contraction and the amount of force exerted by thatcontraction.

Spiral angle 48 is not constant, rather, spiral angle 48 changes withthe distance of a muscle fiber from the outer wall of the ventricle. Theamount of force produced by a muscle fiber is a function of itscontraction, thus, each layer is optimized to produce an optimal amountof force. Since the contraction of each muscle fiber is synchronous withthe increase in the ventricular pressure (caused by the musclecontraction), it might be expected that the muscle fibers produce amaximum force at maximum contraction. However, physiological constraintson muscle fibers denote that maximal force is generated before maximalcontraction. In addition, the force exerted by a muscle fiber begins tofall soon after maximum force is exerted. The varying spiral angle is amechanism which makes it possible to increase the contractile force onthe ventricle after maximum force is reached by a particular musclefiber.

As described above, activation of the heart muscle is from the apex up.Thus, the muscle on the top of the ventricle could theoretically exertmore force than the muscle at apex 46, which would cause a distention atapex 46. The varying spiral angle is one mechanism to avoid distention.Another mechanism is that the muscle near apex 46, which is activatedfirst, is slightly more developed than the muscle at the top of theventricle, which is activated last. As a result of the above describedmechanisms, the force exerted by the ventricular wall is more evenlydistributed over time and space. It should be appreciated that bloodwhich remains in one place without moving, even in the heart, can clot,so it is very important to eject as much blood as possible out of theheart.

As can be appreciated, a complicated mechanism is required tosynchronize the activation of muscle fibers 44 so that an efficient fourphase cycle is achieved. This synchronization mechanism is provided byan electrical conduction system within the heart which conducts anelectrical activation signal from a (natural) cardiac pacemaker tomuscle fibers 44.

FIG. 3 shows the main conduction pathways in heart 20. An SA node 50,located in right atrium 22, generates an activation signal forinitiating contraction of muscle fibers 44. The activation signal istransmitted along a conduction pathway 54 to left atria 26 where theactivation signal is locally disseminated via Bachman bundles and Cristaterminals. The activation signal for contracting the left and rightventricles is conducted from SA node 50 to an AV node 52, where theactivation signal is delayed. The ventricles are normally electricallyinsulated from the atria by non-conducting fibrous tissue, so theactivation signal must travel through special conduction pathways. Aleft ventricle activation signal travels along a left pathway 58 toactivate left ventricle 28 and a right ventricle activation signaltravels along a right pathway 56 to activate right ventricle 24.Generally, the conduction pathways convey the activation signal to apex46 where they are locally disseminated via Purkinje fibers 60 andpropagation over the rest of the heart is achieved by conduction inmuscle fibers 44. In general, the activation of the heart is from theinner surface towards the outer surface. It should be noted thatelectrical conduction in muscle fibers 44 is generally faster along thedirection of the muscle fibers. Thus, the conduction velocity of theactivation signals in heart 20 is generally anisotropic.

As can be appreciated, the delay in AV node 52 results, in a healthyheart, in proper ventricular systolic sequencing. The temporaldistribution of the activation signal in the ventricular muscle resultsin the activation of the ventricles from the apex up. In a healthy heartthe activation signal propagates across left ventricle 28 inapproximately 60 milliseconds. In an externally paced heart, where theactivation signal is not conducted through Purkinje fibers 60 or in adiseased heart, the propagation time is typically longer, such as 150milliseconds. Thus, disease and external pacing affect the activationprofile of the heart.

Cardiac muscle cells usually exhibit a binary reaction to an activationsignal; either the cell responds normally to the activation signal or itdoes not respond at all. FIG. 4 is a graph showing changes in thevoltage of a single cardiac muscle cell in reaction to the activationsignal. The reaction is generally divided into five stages. A rapiddepolarization stage 62 occurs when the muscle cell receives anactivation signal. During this stage, which lasts a few milliseconds,the potential of the cell becomes rapidly positive. Afterdepolarization, the muscle fiber rapidly repolarizes during a rapidrepolarization stage 64 until the cell voltage is approximately zero.During a slow repolarization stage 66, also known as the plateau, themuscle cell contracts. The duration of stage 66, the plateau duration,is directly related to the amount of work performed by the muscle cell.A relatively fast repolarization stage 68 follows, where the muscle cellrepolarizes to its original potential. Stage 66 is also known as therefractory period, during which the cell cannot be activated by anotheractivation signal. During stage 68, the cell is in a relative refractoryperiod, during which the cell can be activated by an exceptionallystrong activation signal. A steady state 70 follows in which the musclecell is ready for another activation.

It should be appreciated that the contraction of cardiac muscle cells isdelayed in time from their activation. In addition the duration of thecontraction is generally equal to the duration of the plateau.

An important factor which may affect the length of the plateau is theexistence of an ionic current resulting from the voltage potentialsgenerated by the local depolarizations. The ionic current starts at thelast activated portion of the heart and progresses back along the pathof the activation. Thus, it is the later activated portions of the heartwhich are first affected by the ionic current. As a result, therepolarization of these cells is relatively faster than therepolarization of the first activated muscle fibers, and theircontraction time is relatively shorter. As can be appreciated, in ahealthy heart, where the propagation time of the activation signal isrelatively short, the ionic currents are significantly smaller than in adiseased or externally paced heart.

One of the main results of the contraction of the ventricles isincreased intra-ventricular pressure. In general, when the intra-cardiacpressure is higher, the outflow from the heart into the circulatorysystem is stronger and the efficiency of the heart is higher. Amathematical relationship termed Laplace's law can be used to model therelationship between the pressure in the ventricle and the tension inthe wall of the ventricle. Laplace's law was formulated for generallyspherical or cylindrical chambers with a distentible wall, however, thelaw can be applied to the ventricles since they are generally elongatedspherical in shape. FIGS. 5A–C show three formulations for determiningthe tension in a portion of the ventricle wall, all of which are basedof the law of Laplace. In FIG. 5A, the tension across a cross-section ofthe wall is shown wherein T, the tension in the wall, is equal to theproduct of P, the transmural pressure across the wall, r (squared), theradius of the ventricle, and π. FIGS. 5B and C show formulas forcalculating the tension per unit in portions of the ventricular wall,for example in FIG. 5C, for a unit cross-sectional area of muscle in awall of thickness δ.

As can be appreciated, if r, the radius of the ventricle, is large, ahigher tension is needed to produce the same pressure change as in aventricle with a smaller radius. This is one of the reasons thatventricular dilation usually leads to heart failure. The heart muscle isrequired to produce a higher tension is order to achieve the samepressure gradient. However, the heart is not capable of producing therequired tension, so, the pressure gradient, and thus the cardiacefficiency, are reduced.

Unfortunately, not all people have healthy hearts and vascular systems.Some types of heart problems are caused by disease. HCM (hypertrophiccardiomyopathy or HOCM) is a disease in which the left ventricle and, inparticular, the ventricular septum, hypertrophy, sometimes to an extentwhich blocks the aortic exit from the left ventricle. Other diseases,such as atrophy causing diseases, reduce the amount of muscle fibers inportions of the heart.

A very common cause of damage to the heart is ischemia of the heartmuscle. This condition, especially when manifesting itself as an acutemyocardial infraction (heart attack), can create dead zones in the heartwhich do not contain active muscle. An additional, and possibly moreimportant effect, is the non-conducting nature of these dead zones whichmay upset the natural activation sequence of the heart. In some cases,damaged heart tissue continues to conduct the activation signal, albeitat a variable or lower velocity, which may cause arrhythmias.

A chronic ischemic condition is usually caused by blockage of thecoronary arteries, usually by arteriosclerosis, which limits the amountof oxygen which can reach portions of the heart muscle. When more work(i.e., more tension) is required of the heart muscle and an increase inoxygen supply is not available, the result is acute pain, and if thesupply is cut off for an extended period, death of the starved musclewill follow.

When the output of the heart is insufficient, a common result ishypertrophy of the heart, usually of the left ventricle. Hypertrophy isa compensatory mechanism of the heart for increasing the output volume.However, in a chronic condition, hypertrophy has generally negativeeffects. For example, arrhythmias, congestive heart failure (CHF) andpermanent changes in the morphology of the heart muscle (ventricularmodeling) may result from hypertrophy.

One of the most common cardiovascular diseases is hypertension. A maineffect of hypertension is increased cardiac output demand, which causeshypertrophy since the blood must be pumped against a higher pressure.Furthermore, hypertension usually aggravates other existing cardiacproblems.

The human heart has many compensatory and adaptive mechanisms, termedcardiac reserve, so that not all cardiac pathologies manifest as heartdisease. Once the cardiac reserve is used up, the heart cannot keep upwith the demand and heart failure may result. One measure of heartfunction and efficiency is the left ventricle ejection factor, which isthe ratio between the amount of blood in the left ventricle duringdiastole and the amount of blood exiting during systole. It should benoted that a significant portion of the change in ventricular volumebetween systole and diastole is due to the thickening of activatedmuscle fibers. Another measure of heart function is the left ventriclestroke volume, which is the amount of blood which is ejected from theleft ventricle each heart beat. It should be noted that once the cardiacreserve is used up it is difficult, if not impossible, for the heart toincrease its output when needed, such as during exercise.

There are many-ways in which non-optimal timing of the activation of theheart can result in lower cardiac output. In AF (atrial fibrillation)one or both atria does not contract in correct sequence with itsassociated ventricle. As a first result, the atria does not inject bloodinto its associated ventricle during atrial systole, so the ventriclevolume is not maximized before ventricular systole, and stroke volume isslightly reduced. If the right atria is fibrillating, sequencing of theAV node is non-regular, which results in the ventricles contracting atan irregular rate, and the heart output is further reduced.

In some cases of a conduction block between the SA node and theventricles, such as caused by a damaged AV node, the contraction of theatria is not synchronized to the contraction of the ventricles, whichalso results in a lower heart output.

Another type of timing deficiency results when there are large deadareas in the heart muscle which do not conduct electrical signals. Theactivation signal must circumvent the dead areas, which results in alonger pathway (and longer delay time) for the activation signalreaching some portions of the heart. In some cases, these portions ofthe heart are activated long after the rest of the heart has alreadycontracted, which results in a reduced contribution of these portions tothe total cardiac output.

Heart muscle which is stressed before it is activated, heart musclewhich is weakened (such as by ischemia) and portions of the heart whichhave turned into scar tissue, may form aneurysms. As can be appreciatedfrom Laplace's law, portions of the ventricle wall which do not generateenough tension to offset the tension induced by the intra-cardiacpressure must increase their local radius in response to the pressureoverload. The stretched wall portion thins out and may burst, resultingin the death of the patient. The apex of the left ventricle isespecially susceptible to aneurysms since it may be very thin. Inaddition, the total pressure in the ventricle and the flow from theventricle are reduced as the aneurysm grows, so the heart output is alsoreduced. Although weak muscle should be expected to hypertrophy inresponse to the greater need, in some cases, such as after an AMI,hypertrophy may not occur before irreversible tissue changes are causedby the stretching.

Perfusion of the heart muscle usually occurs during diastole. However,if the diastole is very long, such as when the activation signal ispropagated slowly, some portions of the heart may not be oxygenatedproperly, resulting in functional ischemia.

As mentioned above, one of the adaptation mechanisms of the heart ishypertrophy, in which the size of the heart increases to answerincreased demand. However, hypertrophy increases the danger ofarrhythmias, which in some cases reduce heart output and in others, suchas VF (ventricular fibrillation) are life threatening. Arrhythmias arealso caused by damaged heart tissues which generate erroneous activationsignals and by blocks in the conduction system of the heart.

In some cases arrhythmias of the heart are treated using medicines, inothers, by implanting a pacemaker or a defibrillator. A common pacemakerimplanting procedure, for example for treating the effects of AF,includes:

(a) ablating or removing the AV node; an

(b) implanting a pacing electrode in the apex of the heart. The locationof the pacing electrode may be changed (during the procedure) if theheart does not beat at a desired sequence for a given output of thepacemaker.

It is also known to pace using multiple electrodes, where the activationsignal is initiated from a selected one or more of the electrodes,depending on sensed electrical values, such as sequence, activation timeand depolarization state. Typically, the pacing regime is adapted to aspecific arrhythmia. Sometimes, logic is included in the pacemaker whichenables it to identify and respond to several types of arrhythmia.

U.S. Pat. No. 5,403,356 to Hill et al. describes a method of preventingatrial arrhythmias by adapting the pacing in the right atrium inresponse to a sensed atrial depolarization, which may indicate anarrhythmia.

Sometimes the pacing is performed for more than one chamber. Forexample, in dual chamber pacing, both left and right ventricles areseparately paced. There have been attempts to use dual chamber pacing torelive aortic obstruction caused by HCM. The aortic exit from the leftventricle is located between the left and right ventricle, so that whenboth ventricles contract simultaneously, the aorta is squeezed from allsides. In a healthy heart, the ventricular septum does not obstruct theaorta, however, in an HCM-diseased heart, the enlarged septum obstructsthe aortic exit from the left ventricle. When pacing to reduce aorticobstruction, the contractions of the left and right ventricles arestepped, so that when the left ventricle contracts, the right ventricledilates and the aorta is less compressed.

Lameh Fananapazir, Neal D. Epstein, Rodolfo V. Curiel, Julio A. Panza,Dorothy Tripodi and Dorothea McAreavey, in “Long-Term Results OfDual-Chamber (DDD) Pacing In Obstructive Hypertrophic Cardiomyopathy”,Circulation, Vol. 90, No. 60, pp. 2731–2742, December 1994, thedisclosure of which is incorporated herein by reference, describes theeffects of pacing a HCM-diseased heart using DDD pacing at the apex ofthe right ventricle. One effect is that the muscle mass near the pacinglocation is reduced, i.e., the ventricular septum is atrophied. Theatrophy is hypothesized to be caused by the changes in workload at thepaced location which are due to the late activation time of ventricularsegments far from the pacing location.

Margarete Hochleitner, Helmut Hortnagl, Heide Hortnagl, Leo Fridrich andFranz Gschnitzer, in “Long-Term Efficiency Of Physiologic Dual-ChamberPacing In The Treatment Of End-Stage Idiopathic Dilated Cardiomyopathy”,American Journal of Cardiology, volume 70, pp. 1320–1325, 1992, thedisclosure of which is incorporated herein by reference, describes theeffect of DDD pacing on hearts which are dilated as a result ofidiopathic dilated cardiomyopathy. DDD pacing resulted in an improvementof cardiac function and in a reduction in hypertrophy in severalpatients. In addition, it is suggested that positioning the ventricularelectrode of the DDD pacemaker in near the apex of the right ventriclereduced the stress at the apex of the left ventricle, by its earlyactivation. No method is suggested for choosing the implantationlocation of the electrodes.

Xavier Jeanrenaud, Jean-Jacques Goy and Lukas Kappenberger, in “EffectsOf Dual Chamber Pacing In Hypertrophic Obstructive Cardiomyopathy”, TheLancet, Vol. 339, pp. 1318–1322, May 30, 1992, the disclosure of whichis incorporated herein by reference, teaches that to ensure success ofDDD pacing in HCM diseased hearts, an optimum AV interval (betweenatrial activation and ventricular activation) is required. In addition,it is suggested that this optimal AV interval is modified by performingexercise.

Several methods may be used to treat heart failure. One method is toconnect assist pumps to the patient's circulatory system, which assistthe heart by circulating the blood. To date, no satisfactory long-termassist pump has been developed. In some cases, a diseased heart isremoved and replaced by another human heart. However, this is anexpensive, complicated and dangerous operation and too few donor heartsare available. Artificial hearts suffer from the same limitations asassist pumps and, like them, are not yet practical.

Certain types of heart failure, such as those caused by conductionblocks in the AV node or by AF can be helped by the implantation of apacemaker, as described above.

Some cases of heart failure can be helped by medicines which eitherstrengthen the heart, correct arrhythmias or reduce the total volume ofblood in the body (which reduces blood pressure): However, many cases ofheart failure can only be treated by reducing the activity of thepatient. Ultimately, once the cardiac reserve is used up, most cases ofheart failure cannot be treated and result in death.

U.S. Pat. No. 5,391,199, the disclosure of which is incorporated hereinby reference, discloses apparatus and method for mapping the electricalactivity of the heart. “Biomedical Engineering Handbook”, ed. Joseph D.Bronzino, chapter 156.3, pp. 2371–2373, IEEE press/CRC press, 1995,describes modeling strategies in cardiac physiology. On page 2373 amodel is described, including experimental support, according to whichmodel the shape of a ventricle is determined by the (local) amount ofoxygen consumption. In addition, this model differentiates betweenpressure overload on the heart, which causes thickening of musclefibers, denoted concentric hypertrophy, and volume overload which causesan increase in the ventricular volume (by stretching), denoted eccentrichypertrophy. Eccentric hypertrophy may also be caused by reducing theamount of oxygen available to the cardiac muscle.

R. S. Reneman, F. W. Prinzen, E. C. Cheriex, T. Arts and T. Delhass, in“Asymmetrical Changes in Left Ventricular Diastolic Wall ThicknessInduced by Chronic Asynchronous Electrical Activation in Man and Dogs”,FASEB J., 1993;7; A752 (abstract), abstract number 4341, the disclosureof which in incorporated herein by reference, describe results ofstudies in paced hearts and which show that earlier activatedventricular wall portions were thinner than later activated wallportions, showing an asymmetrical hypertrophy as a result of the pacing.

C. Daubert, PH. Mabo, Veronique Berder, D. Gras and C. LeClercq, in“Atrial Tachyarrhythmias Associated with High Degree InteratrialConduction Block: Prevention by Permanent Atrial Resynchronisation”,European Journal of C.P.F, Vol. 4, No. 1, pp. 35–44, 1994, thedisclosure of which is incorporated herein by reference, describes amethod of treating atrial fibrillation by implanting pacemakerelectrodes in various locations in the heart, including two electrodesin the right atrium.

Frits W. Prinzen, Cornelis H. Augustijn, Theo Arts, Maurits A. Allessieand Robert Reneman, in “Redistribution of Myocardial Fiber Strain andBlood Flow by Asynchronous Activation”, American Journal of PhysiologyNo. 259 (Heart Circulation Physiology No. 28), H300–H308, 1990, thedisclosure of which is incorporated herein by reference, describesstudies which show that the location of pacing electrodes in a pacedheart significantly affect the distribution of strain, and perfusion(blood flow) in the heart.

SUMMARY OF THE INVENTION

It is an object of some aspects of the present invention to providemethods of augmenting the compensatory mechanisms of the heart.

Another object of some aspects of the present invention is to providemethods of mapping the local physiological values and/or the shape ofthe heart to determine the activation profile of the heart and,preferably, to analyze the resulting maps to determine possibleoptimizations in the activation profile.

Yet another object of some aspects of the present invention is tocontrol the adaptation mechanisms in the heart so that the heart outputor some other parameter of the heart is optimized. Alternatively oradditionally, the adaptation mechanisms of the heart are utilized toeffect change in the morphology of the heart, such as by redistributingmuscle mass.

Still another object of some aspects of the present invention is tocontrol the activation sequence of the heart so that the heart output orsome other physiological variable of the heart is optimized, preferably,in real-time.

When used herein, the terms “physiological variable” and “cardiacparameter” do not include electrical activity, rate, arrhythmia orsequencing of the heart. The term “local physiological value” does notinclude electrical activity, per se, rather it refers to a localphysiological state, such as contraction of local heart muscle,perfusion or thickness. The term “location” refers to a location on orin an object, such as the heart muscle. For example, a valve or an apexof the heart. “Position” refers to a position in space, usually relativeto a known portion of the heart, for example, 1.5 inches perpendicularfrom the apex of the heart. The term “local information” includes anyinformation associated with the location on the heart wall, includingposition and electrical activity.

An object of some aspects of the present invention is related topacemakers which are adapted to control the adaptation mechanisms of theheart and/or to optimize heart parameters.

In a preferred embodiment of the invention, the mechanical motion of theheart muscle is mapped using a catheter having a position sensor nearits distal end. The mapping includes:

(a) placing the catheter into contact with the heart wall;

(b) determining the position of the distal end of the catheter; and

(c) repeating step (b) for additional locations in the heart.

Preferably, the catheter is in contact with the heart wall through theentire cardiac cycle. It should be appreciated that contact with theheart wall can be achieved either from the inside or from the outside 6fthe heart, such as outside contact being achieved by inserting thecatheter into the coronary arteries and/or veins. Alternatively, thecatheter is directly inserted into the body (not through the vascularsystem), such as through a throactoscope or during surgery,

Preferably, (b) includes determining the position of the catheter at atleast two instants of an entire heart cycle. More preferably, itincludes determining the position with time over the cycle.Alternatively or additionally, the catheter has a plurality of distalends, each with a position sensor and (b) includes determining theposition of each one of the ends.

Preferably, the catheter does not move between sequential diastoles.This can be asserted, for example, by using an impedance sensor, bydetermining changes in a locally sensed electrogram, by determining thatthe position sensor repeats its trajectory during heart cycles or bydetermining that the catheter returns to the same location each diastoleor other recognizable portion of the cardiac cycle.

Preferably, the mapping further includes determining the geometry and/orchanges in the geometry of at least a portion of the heart as a functionof time and/or phase of the cardiac cycle. For example, the existence ofan aneurysm can be determined from a characteristic bulge of theaneurysm during systole. Likewise, a dilated ventricle can be determinedfrom the determined volume. Additionally or alternatively, the mappingincludes determining the local radius of a portion of the heart wall.

Preferably the catheter comprises a pressure sensor which measures theintra-cardiac pressure. Further preferably, the forces on the heart wallare calculated using the local radius and/or the determined pressure,preferably using Laplace's law.

Preferably, the catheter includes at least one electrode for determiningthe local electrical activity of the heart. Preferably, the localactivation time and/or the activation signal is measured andincorporated in a map of the heart. Additionally or alternatively, localelectrical conductivity is measured, since fibrous scar tissue does notconduct as well as viable muscle tissue.

A preferred embodiment of the invention provides a map which comparesthe local activation time to the movement of a segment of local heartwall. Preferably, the map compares activation time of the segment tomovement of the segment relative to the movement of surroundingsegments. Thus, the reaction of a muscle segment to the activationsignal can be determined from the local geometrical changes.

In a preferred embodiment of the invention, the instantaneous thicknessof the heart wall at the point of contact is also determined.Preferably, the thickness is measured using an ultrasonic transducer,preferably mounted on the distal portion of the catheter. Preferably,changes in the thickness of the cardiac wall are used to determine thereaction of the heart muscle to the activation signal. Typically, whenthe muscle contracts, the wall thickens, while if the muscle does notreact and the intra-cardiac pressure rises, the wall thins.

In a preferred embodiment of the invention provides a map of the localenergy expenditure of the heart. Preferably, the local energyexpenditure is determined using Laplace's law, local changes inthickness and a pressure sensor, mounted on the catheter, whichdetermines the intra-cardiac pressure.

In preferred embodiments of the invention, additional or alternativesensors are mounted on the distal end of the catheter and are used inconstructing cardiac maps. For example, a Doppler ultrasonic sensorwhich measures perfusion may be used to determine the local perfusion asa function of time and workload. Additionally or alternatively, an ionicsensor is used to sense changes in ion concentrations.

Although the above maps are described as being time based orcardiac-phase based, in a preferred embodiment of the invention,measurements are binned based on geometrical characteristics of theheart or on ECG or electrogram characteristics. Preferably, the ECGcharacteristics comprise pulse rate and/or ECG morphology. Mapsassociated with different bins can be compared to determine pathologiesand under utilization of the heart, for example, an abnormal activationprofile due to a conduction abnormality, such as a block, for assessingthe effects of tachycardia or for assessing changes in the activationprofile as a function of heart rate.

Preferably, maps constructed before a cardiac procedure are compared tomaps constructed after a procedure to determine the effect of theprocedure. In some instances, maps of the heart are constructed whilethe heart is artificially paced.

A preferred embodiment of the invention provides for changing thedistribution of muscle-mass in the heart from an existing muscle-massdistribution to a desired muscle-mass distribution. This is achieved byadjusting the pacing of the heart to achieve an activation profile whichaffects such change. Preferably, portions of the heart which arerelatively atrophied are activated so that relatively more effort isrequired of them than previously. Alternatively or additionally,portions of the heart which are hypertrophied are activated so that lesseffort is required of them than previously. Preferably, the decision howto change the activation profile of the heart is based on a map of theheart, further preferably, using a map which shows the local energyexpenditure and/or the local work performed by each portion of theheart. Alternatively or additionally, a map which shows the ratiobetween local perfusion and local energy expenditure is used.Preferably, the activation profile of the heart is changed when theheart approaches the desired muscle mass distribution. Typically, theheart is paced using an implanted pacemaker. Preferably, a map is usedto determine the optimal location for the pacing electrode(s).Additionally or alternatively, a treatment course of pharmaceuticals foraffecting the activation of the heart, may be designed using such a mapand a model of the reaction of the heart to the pharmaceuticals.

Other cardiac treatment options may also be planned and/or decidedbetween using such maps. For example, bypass surgery is only an optionif the unperfused tissue (whose ischemia will be relived by thesurgery), is viable and its activity (and contribution to the heart)will be improved by the surgery. Thus, before deciding between bypasssurgery, PCTA and other reperfusion treatments, it is possible toacquire and analyze a map to help with the decision. In one example,tissue which induces arrhythmia due to ischemia can be detected using amap of the types described herein and a decision to reperfuse made. Inanother example, performing bypass surgery to increase perfusion to scartissue, is traumatic to the patient and may actually reduce theperfusion of other parts of the heart. If, before the surgery, a map isconsulted, unnecessary surgery may be averted or at least reduced incomplexity (double instead of triple bypass)

One aspect of the invention relates to the optimal placement ofpacemaker electrodes. A preferred method of determining electrodeplacement includes:

(a) pacing a heart from a first location;

(b) determining a value of a physiological variable while pacing at thefirst location;

(c) repeating (a) and (b) at least at a second location; and

(d) implanting the pacing electrode at a location of the first andsecond locations which yields an optimal value for the physiologicalvariable or at a location with a response known to yield an optimalvalue in the future.

One preferred physiological variable is the stroke volume. Preferably,the physiological variable is measured using a catheter.

Yet another aspect of the invention relates to pacing a heart to reducestress. A preferred method of pacing the heart includes:

(a) measuring a local physiological value at a plurality of locations inthe heart;

(b) determining a pacing regime which will change the distribution ofthe value at the plurality of locations; and

(c) pacing the heart using the new pacing regime.

Preferably, the new pacing regime is determined such that the stress oncertain portions of the heart will be reduced, preferably, by keepingthe local physiological value within a range. Further preferably, therange is locally determined based on local conditions in the heart. Onepreferred local physiological value is blood perfusion. Preferably,(a)–(c) are performed substantially in real time. Further preferably,measuring the physiological value is performed substantiallysimultaneously at the plurality of locations.

Still another aspect of the invention relates to increasing theefficiency of a heart using adaptive pacing. A preferred method ofadaptive pacing includes:

(a) determining a preferred pacing regime for a heart which is optimalwith respect to a physiological variable; and

(b) pacing the heart using the preferred pacing regime.

Preferably, the preferred pacing regime is determined using a map of theheart. The map is preferably analyzed to determine which portions of theheart are under-utilized due to their activation time. The preferredpacing is preferably initiated by implanting a pacer, preferably, with aplurality of electrodes. Alternatively or additionally, the preferredpacing is initiated by changing the electrification of a plurality ofpreviously implanted pacemaker electrodes.

In a preferred embodiment of the invention, the pacing regime isregularly changed so that each pacing regime optimizes the utilizationof different portions of the heart. Additionally or alternatively, thepacing regime is regularly changed to temporally distribute workloadbetween different portions of the heart.

Another aspect of the invention relates to pacemakers having adaptivepacing regimes. A preferred pacemaker includes:

a plurality of electrodes;

a source of electricity for electrifying the electrodes; and

a controller which changes the electrification of the electrodes inresponse to a plurality of measured local physiological values of aheart to achieve an optimization of a physiological variable of theheart.

The measured physiological values preferably include plateau lengthand/or activation time. Preferably, the measurement is performed usingthe pacemaker electrodes. Alternatively or additionally, measurement isperformed using at least one additional sensor. One preferredphysiological variable is stroke volume. Further preferably, thephysiological variable is measured by the pacemaker, such as measuringintra-cardiac pressure using a solid-state pressure sensor.

There is therefore provided in accordance with a preferred embodiment ofthe invention, a method of constructing a cardiac map of a heart havinga heart cycle including:

(a) bringing an invasive probe into contact with a location on a wall ofthe heart;

(b) determining, at at least two different phases of the heart cycle, aposition of the invasive probe;

(c) determining a local non-electrical physiological value at thelocation;

(d) repeating (a)–(c) for a plurality of locations of the heart; and

(e) combining the positions to form a time-dependent map of at least aportion of the heart. Preferably, the method includes:

(f) determining at least one local relationship between changes inpositions of the invasive probe and a determined local non-electricalphysiological value.

There is provided in accordance with another preferred embodiment of theinvention, a method of constructing a cardiac map of a heart having aheart cycle including:

(a) bringing an invasive probe into contact with a location on a wall ofthe heart;

(b) determining a position of the invasive probe;

(c) determining a local non-electrical physiological value at thelocation at a plurality of different phases of the heart cycle;

(d) repeating (a)–(c) for a plurality of locations of the heart; and

(e) combining the positions to form a map of at least a portion of theheart. Preferably, the method includes determining at least a secondposition of the invasive probe at a phase at which the localnon-electrical value is found, which position is different from theposition determined in (b). Preferably, the method includes determiningat least one local relationship between changes in positions of theinvasive probe and determined local non-electrical physiological values.

Preferably, the method includes determining a trajectory of the probe asa function of the cardiac cycle. Preferably, the method includesanalyzing the trajectory.

Additionally or alternatively, the local physiological value isdetermined using a sensor external to the probe. Preferably, the sensoris external to a body which includes the heart. Alternatively, the localphysiological value is determined using a sensor in the invasive probe.Alternatively or additionally, the local physiological value isdetermined at substantially the same time as the position of theinvasive probe. Alternatively or additionally, the map includes aplurality of maps, each of which corresponds to a different phase of thecycle of the heart. Alternatively or additionally, the map includes adifference map between two maps, each of which corresponds to adifferent phase of the cycle of the heart. Alternatively oradditionally, the local physiological value includes a chemicalconcentration.

Alternatively or additionally, the local physiological value includes athickness of the heart at the location. Preferably, the thickness of theheart is determined using an ultrasonic transducer mounted on theinvasive probe. Preferably, the method includes determining a reactionof the heart to an activation signal by analyzing changes in thethickness of the heart.

Alternatively or additionally, the local physiological value includes ameasure of a perfusion at the location. Alternatively or additionally,the local physiological value includes a measure of work performed atthe location. Alternatively or additionally, the method includesdetermining a local electrical activity at each of the plurality oflocations of the heart. Preferably, the electrical activity includes alocal electrogram. Alternatively or additionally, the electricalactivity includes a local activation time. Alternatively oradditionally, the electrical activity includes a local plateau durationof heart tissue at the location. Alternatively or additionally, theelectrical activity includes a peak-to-peak value of a localelectrogram.

Alternatively or additionally, the method includes determining a localchange in the geometry of the heart. Preferably, the local changeincludes a change in a size of an area surrounding the location.Alternatively or additionally, the local change includes a warp of anarea surrounding the location. Alternatively or additionally, the localchange includes a change in a local radius of the heart at the location.Preferably, the method includes determining an intracardiac pressure ofthe heart. Preferably, the method includes determining a relativetension at the location. Preferably, the relative tension is determinedusing Laplace's law.

In a preferred embodiment of the invention, the method includesdetermining an absolute tension at the location.

In a preferred embodiment of the invention, the method includesdetermining a movement of the location on the heart wall relative to themovement of neighboring locations. Alternatively or additionally, themethod includes determining the activity of the heart at the location.Preferably, determining the activity includes determining a relativemotion profile of the location on the heart wall relative to neighboringlocations. Alternatively, the activity includes determining a motionprofile of the heart at the location.

In a preferred embodiment of the invention, the method includesmonitoring stability of the contact between the invasive probe and theheart. Preferably, monitoring includes monitoring the stability of thecontact between the probe and the heart based on the motion profile.Alternatively or additionally, monitoring includes detecting changes inthe motion profile for different heart cycles. Alternatively oradditionally, monitoring includes detecting differences in positions ofthe probe at the same phase for different heart cycles. Alternatively oradditionally, monitoring includes detecting changes in a locallymeasured impedance of the invasive probe to a ground. Alternatively oradditionally, monitoring includes detecting artifacts in a locallydetermined electrogram.

In a preferred embodiment of the invention, the method includesreconstructing a surface of a portion of the heart. Alternatively oradditionally, the method includes binning local information according tocharacteristics of the cycle of the heart. Preferably, thecharacteristics include a heart rate. Alternatively or additionally, thecharacteristics include a morphology of an ECG of the heart. Preferably,the ECG is a local electrogram. Alternatively or additionally, themethod includes separately combining the information in each bin into amap. Preferably, the method includes determining differences between themaps.

In a preferred embodiment of the invention, the positions of theinvasive probe are positions relative to a reference location.Preferably, the reference location is a predetermined portion of theheart. Alternatively or additionally, a position of the reference isdetermined using a position sensor. Alternatively or additionally, themethod includes periodically determining a position of the referencelocation. Preferably, the position of the reference location is acquiredat the same phase in different cardiac cycles.

In a preferred embodiment of the invention, the invasive probe islocated in a coronary vein or artery. Alternatively, the invasive probeis located outside a blood vessel.

In a preferred embodiment of the invention, local information isaveraged over a plurality of cycles.

There is also provided in accordance with a preferred embodiment of theinvention, a method of determining the effect of a treatment includingconstructing a first map of a heart, prior to the treatment;constructing a second map of the heart, after the treatment; andcomparing the first and second maps to diagnose the effect of thetreatment.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to determine underutilized portions of the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to select a procedure for treating the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to determine optimization possibilities in the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to determine underperfused portions of the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to determine overstressed portions of the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to determine local pathologies in the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method including constructing a map of a heart; andanalyzing the map to assess the viability of portions of the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method of determining the effect of a change in activationof a heart, including constructing a first map of a heart, prior to thechange; constructing a second map of the heart, after the change; andcomparing the first and second maps to diagnose the effect of the changein activation.

There is also provided in accordance with a preferred embodiment of theinvention, a method of determining the effect of a change in activationof a heart, including constructing a first map of a heart, prior to thechange; constructing a second map of the heart, after the change;constructing a second map of the heart; and comparing the first andsecond maps, wherein the two maps are acquired in parallel by acquiringlocal information at a location over several cardiac cycles, wherein theactivation changes during the several cardiac cycles.

There is also provided in accordance with a preferred embodiment of theinvention, a method of assessing viability including constructing afirst map of a heart, prior to a change in activation of the heart;constructing a second map of the heart, after the change; and comparingthe first and second maps to assess the viability of portions of theheart. Preferably, changing the activation includes changing a pacing ofthe heart. Alternatively or additionally, changing the activationincludes subjecting the heart to chemical stress. Alternatively oradditionally, changing the activation includes subjecting the heart tophysiological stress.

In a preferred embodiment of the invention, the heart is artificiallypaced.

There is also provided in accordance with a preferred embodiment of theinvention, a method of cardiac shaping including generating a map of aheart; choosing a portion of the heart having a certain amount of muscletissue thereat; and determining a pacing regime for changing theworkload of the portion. Preferably, the method includes pacing theheart using the determined pacing regime. Preferably, the methodincludes waiting a period of time; then determining the effect of thepacing regime; and repeating choosing, determining and pacing if adesired effect is not reached. Preferably, the workload of the portionis increased in order to increase the amount of muscle tissue therein.Alternatively, the workload of the portion is decreased in order todecrease the amount of muscle tissue thereat. In a preferred embodimentof the invention, the workload is changed by changing an activation timeof the portion. Preferably, the map includes electrical activationinformation. Alternatively or additionally, the map includes mechanicalactivation information.

There is also provided in accordance with a preferred embodiment of theinvention, a method of determining an optimal location for implanting apacemaker electrode including:

(a) pacing a heart from a first location;

(b) determining a cardiac parameter associated with pacing at thelocation; and

(c) repeating (a) and (b) for a second location; and

(d) selecting an optimal location based on the determined values for thecardiac parameters. Preferably, the method includes:

(e) implanting the electrode at the location for which the cardiacparameter is optimal.

Preferably, pacing a heart includes bringing an invasive probe having anelectrode to a first location and electrifying the electrode with apacing current.

Preferably, the cardiac parameter includes stroke volume. Alternativelyor additionally, the cardiac parameter includes intra-cardiac pressure.Alternatively or additionally, determining the cardiac parameterincludes measuring the cardiac parameter using an invasive probe.

There is also provided in accordance with a preferred embodiment of theinvention, a method of determining a regime for pacing a heart,including:

(a) determining a local physiological value at a plurality of locationsin the heart; and

(b) determining a pacing regime which changes a distribution of thephysiological value in a desired manner. Preferably, the distributionincludes a temporal distribution. Alternatively or additionally, thedistribution includes a spatial distribution. Preferably, the methodincludes pacing the heart using the determined pacing regime.Alternatively or additionally, changing the distribution includesmaintaining physiological values within a given range. Preferably, therange includes a locally determined range. Alternatively oradditionally, the range includes a phase dependent range, whereby adifferent range is preferred for each phase of a cardiac cycle.Alternatively or additionally, the range includes an activationdependent range, whereby a different range is preferred for eachactivation profile of the heart. Preferably, different heart rates havedifferent ranges. Alternatively or additionally, different arrhythmiastates have different ranges.

In a preferred embodiment of the invention, the physiological values aredetermined substantially simultaneously. Preferably, the physiologicalvalue includes perfusion. Alternatively or additionally, thephysiological value includes stress. Alternatively or additionally, thephysiological value includes plateau duration.

There is also provided in accordance with a preferred embodiment of theinvention, a method of determining a preferred pacing regime, includinggenerating a map of the heart; and determining, using the map, apreferred pacing regime for a heart which is optimal with respect to aphysiological variable. Preferably, the method includes pacing the heartusing the preferred pacing regime. Alternatively or additionally, themap includes an electrical map. Preferably, determining a preferredpacing regime includes generating a map of the activation profile of theheart. Alternatively or additionally, the map includes a mechanical map.Preferably, determining a preferred pacing regime includes generating amap of the reaction profile of the heart. Alternatively or additionally,the method includes analyzing an activation map or a reaction map of theheart to determine portions of the heart which are under-utilized due toan existing activation profile of the heart. Alternatively oradditionally, pacing is initiated by implanting at least one pacemakerelectrode in the heart. Preferably, the at least one pacemaker electrodeincludes a plurality of individual electrodes, each attached to adifferent portion of the heart.

In a preferred embodiment of the invention, pacing is initiated bychanging the electrification of a plurality of previously implantedpacemaker electrodes. Alternatively or additionally, the physiologicalvariable includes a stroke volume. Alternatively or additionally, thephysiological variable includes a ventricular pressure profile.

There is also provided in accordance with a preferred embodiment of theinvention, a method of pacing including:

(a) pacing a heart using a first pacing scheme; and

(b) changing the pacing scheme to a second pacing scheme, wherein thechange in pacing is not directly related to a sensed or predictedarrhythmia, fibrillation or cardiac output demand in the heart.Preferably, each of the pacing regimes optimizes the utilization ofdifferent portions of the heart. Alternatively or additionally, thechanging of the pacing regimes temporally distributes workload betweendifferent portions of the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a pacemaker which performs any of the above described pacingbased methods.

There is also provided in accordance with a preferred embodiment of theinvention, a pacemaker including: a plurality of electrodes; a source ofelectricity for electrifying the electrodes; and a controller whichchanges the electrification of the electrodes in response to a pluralityof values of local information of a heart, measured at differentlocations, to achieve an optimization of a cardiac parameter of theheart. Preferably, the local information is measured using theelectrodes. Alternatively or additionally, the local information ismeasured using a sensor.

There is also provided in accordance with a preferred embodiment of theinvention, a pacemaker including a plurality of electrodes; a source ofelectricity for electrifying the electrodes; and a controller whichchanges the electrification of the electrodes in response to a storedmap of values of local information of a heart at different locations, toachieve an optimization of a cardiac parameter of the heart.

Preferably, the local information includes a local activation time.Alternatively or additionally, the local information includes a localplateau duration. Alternatively or additionally, the local informationincludes local physiological values. Alternatively or additionally, thelocal information includes phase dependent local positions.Alternatively or additionally, the cardiac parameter includes a strokevolume. Alternatively or additionally, the cardiac parameter is measuredby the pacemaker. Alternatively or additionally, the cardiac parameterincludes an intracardiac pressure.

There is also provided in accordance with a preferred embodiment of theinvention, a method of detecting structural anomalies in a heart,including:

(a) bringing an invasive probe into contact with a location on a wall ofthe heart;

(b) determining a position of the invasive probe;

(c) repeating (a)–(b) for a plurality of locations on the wall;

(d) combining the positions to form a time-dependent map of at least aportion of the heart; and

(e) analyzing the map to determine structural anomalies in the heart.Preferably, the structural anomaly is an insipid aneurysm.

Preferably, the method includes repeating (b) at least a second time, atthe same location and at a different phase of the cardiac cycle than(b).

There is also provided in accordance with a preferred embodiment of theinvention, a method of adding a conductive pathway in a heart between afirst segment of the heart and a second segment of the heart, including:generating a mechanical map of the heart; providing an activationconduction device having a distal end and a proximal end; electricallyconnecting the distal end of the device to the first segment; andelectrically connecting the proximal end of the device to the secondsegment.

There is also provided in accordance with a preferred embodiment of theinvention, a conductive device for creating conductive pathways in theheart, including: a first lead adapted for electrical connection to afirst portion of the heart; a second lead adapted for electricalconnection to a second portion of the heart; a capacitor for storingelectrical charge generated at the first portion of the heart and fordischarging the electrical charge at the second portion of the heart.

There is also provided in accordance with a preferred embodiment of theinvention, a method of viewing a map, including: providing a map oflocal information of a heart; and overlaying a medical image on the map.Preferably, the medical image is an angiogram. Alternatively oradditionally, the medical image is a three-dimensional image.Alternatively or additionally, the map contains both spatial andtemporal information.

There is also provided in accordance with a preferred embodiment of theinvention, a method of diagnosis including: generating a map of a heart;and correlating the map with a library of maps. Preferably, the methodincludes diagnosing the condition of the heart based on the correlation.

There is also provided in accordance with a preferred embodiment of theinvention, apparatus including: a memory having a plurality of mapsstored therein; and a correlator which correlates an input map with theplurality of maps.

There is also provided in accordance with a preferred embodiment of theinvention, a method of analysis, including generating a map ofelectrical activation of a heart; generating a map of mechanicalactivation of the heart; and determining local relationships between thelocal electrical activation and mechanical activation. Preferably, themechanical activation includes a profile of movement. Preferably, theelectrical activation includes an activation time.

There is also provided in accordance with a preferred embodiment of theinvention, apparatus adapted to generate a map in accordance with any ofthe mapping methods described herein. Preferably, the apparatus includesa display adapted to display the map.

Although the description of the present invention focuses on the heart,apparatus and methods described herein are also useful for mapping andaffecting other organs, such as the stomach and other muscles. Forexample, in treating atrophied muscles using stimulation, anelectromechanical map of the muscle is preferably acquired during a teststimulation to help in determining and optimal stimulation regime.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic cross-section diagram of a heart;

FIGS. 1B–1E are schematic cross-section diagrams showing the heart ineach of four phases of a cardiac cycle;

FIG. 1F is a graph showing the blood volume in a left ventricle of theheart during a cardiac cycle;

FIG. 1G is a graph showing the filling rate of the left ventricle duringa cardiac cycle;

FIG. 2 is a partial schematic view of a heart showing the arrangement ofcardiac muscle fibers around a left ventricle;

FIG. 3 is a schematic cross-section diagram of a heart showing theelectrical conduction system of the heart;

FIG. 4 is a graph showing changes in the voltage potential of a singlecardiac muscle cell in reaction to an activation signal;

FIGS. 5A–C are partial schematic cross-sectional perspective views of aheart showing application of Laplace's law to the determination oftension in the heart muscle;

FIG. 6 is a schematic cross-sectional side view of a heart showing apreferred apparatus for generating a map of the heart;

FIG. 7 is a flowchart of a preferred method of constructing the maputilizing the apparatus of FIG. 6;

FIG. 8 is a generalized graph showing the dependence of a resistance onthe distance of the catheter from heart muscle tissue;

FIGS. 9A–D show various local changes in the geometry of the heart;

FIG. 10 shows a multi-headed catheter for sensing local geometricchanges according to a preferred embodiment of the invention;

FIG. 11 is a flowchart showing a preferred binning method;

FIGS. 12A–D show pathological cases where a change in pacing of a heartis desirable; and

FIG. 13 is a schematic side view of an implanted pacemaker according toa preferred embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A first preferred embodiment of the invention relates to mapping thegeometry of the heart and time related changes in the geometry of theheart. FIG. 6 is a schematic side view of a preferred apparatus forperforming the mapping. FIG. 7 is a flowchart showing a preferred methodfor performing a mapping.

Referring to FIG. 6, a distal tip 74 of a mapping catheter 72 isinserted into heart 20 and brought into contact with heart 20 at alocation 75. Preferably, the position of tip 74 is determined using aposition sensor 76. Sensor 76 is preferably a position sensor asdescribed in PCT application US95/01103, “Medical diagnosis, treatmentand imaging systems”, filed Jan. 24, 1995, in U.S. Pat. No. 5,391,199 orin U.S. Pat. No. 5,443,489, all assigned to the same assignee as theinstant application and the disclosures of which are incorporated hereinby reference, and which typically require an external magnetic fieldgenerator 73. Alternatively, other position sensors as known in the artare used, for example, ultrasonic, RF and rotating magnetic fieldsensors. Alternatively or additionally, tip 74 is marked with a markerwhose position can be determined from outside of heart 20, for example,a radio-opaque marker for use with a fluoroscope. Preferably, at leastone reference catheter 78 is inserted into heart 20 and placed in afixed position relative to heart 20. By comparing the positions ofcatheter 72 and catheter 78, the position of tip 74 relative to theheart can be accurately determined even if heart 20 exhibits overallmotion within the chest. Preferably the positions are compared at leastonce every cardiac cycle, more preferably, during diastole.Alternatively, position sensor 76 determines the position of tip 74relative to catheter 78, for example, using ultrasound, so no externalsensor or generator 73 is required. Alternatively, catheter 78 isoutside the heart, such as outside the body or in the esophagus.

It should be appreciated that a geometric map can be constructed even ifposition sensor 76 only determines position and not orientation.However, since sensor 76 is typically located at a small distance fromtip 74, at least two orientation angles are desirable to increase theaccuracy of the position determination of tip 74.

Referring to FIG. 7, a typical mapping process includes:

(a) bringing catheter tip 74 into contact with the wall of heart 20, atlocation 75;

(b) determining at least one position of tip 74;

(c) adding the position value to the map;

(d) moving catheter 72 to a second location, such as a location 77;

(e) repeating steps (b)–(d); and

(f) (optionally) reconstructing the surface of heart 20 from thedetermined positions.

Reconstructing the surface of heart 20 may comprise reconstructing inneror outer surfaces of heart 20, depending on the location of catheter tip74. Methods of reconstructing a surface from a plurality of data pointsare well known in the art.

Preferably, catheter 72 is a steerable tip catheter, so thatrepositioning of tip 74 is facilitated. Steerable catheters are furtherdescribed in PCT application US95/01103 and in U.S. Pat. Nos. 5,404,297,5,368,592, 5,431,168, 5,383,923, 5,368,564, 4,921,482, 5,195,968, thedisclosures of which are incorporated herein by reference.

In a preferred embodiment of the invention, each position value has anassociated time value, preferably relative to a predetermined point inthe cardiac cycle. Preferably, multiple position determinations areperformed, at different points in the cardiac cycle, for each placementof tip 74. Thus, a geometric map comprises a plurality of geometricsnapshots of heart 20, each snapshot associated with a different instantof the cardiac cycle. The cardiac cycle is preferably determined using astandard ECG device. Alternatively or additionally, a local referenceactivation time is determined using an electrode on catheter 72. Heart20 may be paced in a known manner, such as by catheter 78 or may benaturally paced.

In an alternative preferred embodiment of the invention, position valuesare acquired also while tip 74 is not in contact with heart 20. Theseposition values can be used to help generation of an image of the innersurface of heart 20 by a process of elimination, since any point insidethe heart, not in contact with the surface, is not on its inner surface.

As can be appreciated, contact between tip 74 and heart 20 must beassured. In particular, it is important to know when tip 74 comes intocontact with heart 20 after repositioning of tip 74 and the stability oftip 74 at a location, such as whether tip 74 moves from location 75without operator intervention as a result of motion of heart 20 must beknown. One method of monitoring the contact between tip 74 and location75 is through analysis of the trajectory of tip 74. The inner wall ofheart 20 has many crevices and tip 74 typically lodges in one of thesecrevices, such that tip 74 moving together with location 75. It can beexpected that tip 74 will return to the same spatial position eachcardiac cycle. Thus, if tip 74 does not return to the same position eachdiastole, contact between tip 74 and location 75 is not stable. Further,some types of slippage can be detected by determining whether the entiretrajectory of tip 74 substantially repeats itself Furthermore, sometypes of slippage add artifacts to the trajectory which can be detectedby comparing the trajectory against trajectories of nearby segments ofthe heart or against a model of the motion of the heart.

It is also known that initiation of contact between tip 74 and heart 20causes artifacts in a locally measured electrogram. Thus, in a preferredembodiment of the invention, tip 74 includes an electrode 79 whichmeasures the local electrical activity. Artifacts in the measuredactivity indicate that tip 74 is not in stable contact with location 75.Preferably, the local electrical activity and in particular, the localactivation time and local plateau length, are stored in association witheach location in heart 20.

In an additional embodiment of the invention, the contact pressurebetween tip 74 and location 75 is measured, using a pressure sensor, todetermine the existence and stability of contact therebetween.

In a preferred embodiment of the invention electrode 79 is used tomeasure the impedance between tip 74 and a ground outside the patient.The impedance between tip 74 and the ground is affected by the distanceof tip 74 from the wall of heart and by the quality of contacttherebetween. The effect can be explained in the following manner. Longcells such as muscle cells and nerves exhibit electrical conductivitieswhich are non-isotropic and frequency dependent. Blood, which fillsheart 20, exhibits conduction which is relatively frequency independentand isotropic, and its resistance is approximately half the averageresistance of muscle tissue. The greatest amount of frequency dependenceof body structures is found between 30 and 200 Hz. However, frequenciesin the range 30 Hz–10 MHz are useful. For example, at 50 KHz, contactcan be most easily determined from changes in the impedance and at 0.5MHz, accumulation of residue on the catheter from charring of heartmuscle during ablation can be determined from changes in the impedance.

FIG. 8 is a generalized graph showing the dependence of a resistance,between tip 74 and an external lead attached to the patient, on thedistance of tip 74 from location 75, at 50 KHz.

Local geometric changes in the heart are also clinically interesting.FIG. 9A shows a segment 90 of heart 20 and FIGS. 9B–9D show variousaspects of local movement of segment 90. The timing of movement ofsegment 90 relative to the cardiac cycle and/or relative to the movementof other segments of heart 20 indicates forces acting at segment 90.These forces may be as a result of local contraction at segment 90 or asa result of contraction of other portions of heart 20. Movement ofsegment 90 before an activation signal reaches segment 90 may indicatethat segment 90 is not activated at an optimal time and, thus, that itdoes not contribute a maximum amount to the output of heart 20. Movementwithout an activation signal usually indicates non-muscular tissue, suchas scar tissue. The activation time is preferably measured usingelectrode 79 (FIG. 6).

FIG. 9B shows another way of determining the reaction of muscle tissueto an activation signal. A first location 92 is located a distance D1from a second location 94 and a distance D2 from a third location 96. Ina normal heart D1 and D2 can be expected to contract at substantiallythe same time by a substantially equal amount. However, if the tissuebetween location 92 and location 94 is non-reactive, D1 might even growwhen D2 contracts (Laplace's law). In addition a time lag between thecontraction of D1 and of D2 is probably due to blocks in the conductionof the activation signal. A map of the reaction of the heart to anactivation signal may be as important as an activation map, since it isthe reaction which directly affects the cardiac output, not theactivation.

FIGS. 9C and 9D show the determination of local changes in the radius ofheart 20, which can be together with the pressure to determine the localtension using Laplace's law. In FIG. 9C a plurality of locations 98, 100and 102 exhibit a local radius R1 and in FIG. 9D, the local radiusdecreases to R2, which indicates that the muscle fiber at locations 98,100 and 102 is viable. It should be noted, that since the pressure inheart 20 is spatially equalized, a ratio between the tension atdifferent parts of heart 20 can be determined even if an absolute valuecannot be determined.

In a preferred embodiment of the invention, a plurality of catheters areplaced at locations 98, 100 and 102, so that changes in the localgeometry can be determined in a single cardiac cycle. Alternatively oradditionally, a multi-head catheter, each head having a position sensor,is used to map local geometrical changes. FIG. 10 shows a multi-headcatheter 104 having a plurality of position sensors 106 for mappinglocal geometric changes.

Another clinically important local change is a change in the thicknessof a wall segment of heart 20. Muscle fibers thicken when they contract,so an increase in the thickness of the wall segment indicates thatmuscle fibers in the wall segment are contracting. Thinning of the wallsegment indicates that the wall segment is stretching. Either there arenot enough muscle fibers in the wall segment to overcome the tension onthe wall segment or the muscle fibers in the wall segment are notactivated in synchrony with the rest of heart 20, resulting in pressureincreases which are not counteracted by local tension increases. Lateincreases in the thickness of the wall segment usually indicate that theactivation signal was delayed at the segment. Local changes in thicknesscan also be compared to a locally determined activation time, todetermine a local reaction time. In addition, comparison of differencesin thickening between several adjacent wall segments is indicative ofthe activation time, much like changes in local geometry.

The local thickness of the wall segment is preferably determined usingan ultrasonic sensor mounted on catheter 72 or catheter 78. Forwardlooking ultrasonic sensors (FLUS), suitable for mounting on catheter 72for determining the local thickness of the wall segment are described inPCT application US95/01103 and in U.S. Pat. No. 5,373,849, thedisclosures of which are incorporated therein by reference. A sidelooking ultrasonic sensor (SLUS), suitable for mounting on catheter 78is described in PCT publication WO 95/07657, the disclosure of which isincorporated herein by reference. Alternatively or additionally, anexternal sensor, such as an echocardiograph determines the thickness ofthe wall segment adjacent tip 94.

In a preferred embodiment of the invention sensors, additional toposition sensor 76, are mounted at tip 74. As already described, atleast one electrode 79 is preferably mounted at tip 74 to map the localelectrical activity which can be integrated with the geometric map toform an electromechanical map. For example, contraction duration can becompared to local electrical plateau length or local activation time canbe compared to local reaction time using an electromechanical map.

Additionally or alternatively, a chemical sensor is mounted at tip 74 todetermine changes in the local ionic concentrations or local chemicalconcentrations. Typically, such a chemical sensor is mounted on a needlewhich is inserted into the myocardium.

Alternatively or additionally, a perfusion meter is mounted on tip 74 todetermine the amount of perfusion. Examples of perfusion meters include:a Doppler ultrasound perfusion meter or a Doppler laser perfusion meter,such as disclosed in “Design for an ultrasound-based instrument formeasurement of tissue blood flow”, by Burns, S. M. and Reid, M. H., inBiomaterials. Artificial Cells and Artificial Organs, Volume 17, Issue 1page 61–68, 1989, the disclosure of which is incorporated herein byreference. Such a perfusion meter preferably indicates the flow volumeand/or the flow velocity.

Alternatively or additionally, a scintillation detector is mounted ontip 74 to detect radiation emitted by radio-pharmaceuticals injectedinto or ingested by the patient. If a suitable low energyradio-pharmaceutical is used, the scintillation detector will besensitive to radiation from portions of heart 20 substantially incontact with tip 74. For example, local perfusion can be determined.

In another preferred embodiment of the invention, an optical sensor ismounted on tip 74. As is known in the art, oxygenated blood reflects aspectrum which is different from the spectrum reflected bynon-oxygenated blood. By determining the reflectance of portions ofheart 20, the perfusion thereof can be determined. Additionally oralternatively, optical reflectivity patterns or texture is used todifferentiate between different tissue types, for example, fibrous,viable muscle and damaged muscle. Preferably, the optical sensor is acamera or a fiber-optic image guide. Further preferably, an IR(infra-red) sensitive sensor is used. Typically, illumination at tip 74is provided by a light source mounted on tip 74 or by light transmittedthrough a fiber-optic light-guide.

Alternatively or additionally, a cold-tip catheter is used to map theeffect of ablating a portion of the heart. It is known in the art thathypothermic cardiac muscle does not initiate or react to electricalsignals. Cold-tip catheters, such as disclosed in PCT publication WO95/19738 of Jul. 25, 1995, the disclosure of which is incorporatedherein by reference, can be used to inhibit the electrical activity of alocal wall segment while simultaneously mapping the local geometricaleffects of the inhibition.

Other locally sensed variables include, temperature, which may indicateperfusion or activation, osmolarity, conduction velocity, repolarizationtime, repolarization duration, and impedance, which may indicate tissuetype and viability.

Mapping is typically performed when heart 20 is externally paced, suchas using another catheter, either to set a constant heart rate or togenerate certain arrhythmias. Electrode 79 is useful in identifying andanalyzing arrhythmias. In addition electrode 79 can be used as apacemaker to determine the effect of pacing from a certain location,such as initiating VT. The location of the catheter may be displayed asa relatively fixed location, such as end diastolic position.Alternatively, the movement of the catheter with the cardiac cycle isshown (with or without a changing map of the heart) as a navigationalaid.

Several types of maps are generally acquired. One type maps localphysiological values as a function of location on the heart, for exampleconductance. In this type of map, the position of tip 74 is typicallydetermined at the same phase of the cardiac cycle for each new locationand is unrelated to the acquisition of the local value. The local valuemay be time dependent. For example, a map of the instant local thicknessof the heart wall as a function of the phase of the cardiac cycle.Another example is a local electrogram as a function of time. The valuemay be continuously acquired over the entire cardiac cycle, only over aportion thereof or at a single instant synchronized to the positiondetermination and/or the cardiac cycle. A geometric map includesinformation about the geometry of the heart, for example shape andvolume, and/or changes in the geometry of the heart as a function oftime, for example, thickness, local curvature and shape. Anelectro-mechanical map includes information about the coupling betweenelectrical signals and mechanical changes in the heart, for example,thickening as a function of activation time. Other types of maps includechemical-mechanical maps, which correlate mechanical and chemical actionof the heart, energy expenditure maps which show local expenditures ofenergy, perfusion maps which show local perfusion of cardiac muscle anda map of the ratio between energy expenditure and local perfusion. Oneimportant type of map displays the delay between electrical activationtime and various parameters of mechanical reaction. The mechanicalreaction displayed may be a start of contraction, a maximum contractionor an end of contraction. Further, such a map may show the relativedelays between any portion of the local electrical activity and themechanical activity, for example, the electrical activity may be the endof the plateau or the beginning of the rapid depolarization. Thisinformation is useful in differentiated between healthy and diseasedtissue, as the lag between electrical and mechanical activity tends tobe more pronounced in diseased tissue.

Several different types of analysis are useful in preferred embodimentsof the invention. In one, basic type of analysis, acquisition of localinformation is repeated at the same point over a number of cycles forbinning. Preferably, the pacing of the heart is changed between theacquisitions and each measured value is associated with a particularpacing regime. Alternatively, this type of analysis may be practicedwhile performing ablations in the heart or otherwise changing theactivation profile of the heart. Alternatively, the acquired values areaveraged over several cardiac cycles to reduce noise.

In accordance with another preferred embodiment of the invention, thetrajectory of the catheter is analyzed over a period of several cardiaccycles. This analysis is useful to determine changes in the activationprofile of the heart over time or as a function of respiration and bodyposition.

In a preferred embodiment of the invention, one or more different typesof local analysis may be performed to assess cardiac function, locallyand as a whole. One type of local analysis determines the location,velocity and or acceleration of the probe as a function of the cardiaccycle. Also, local voltage or any other type of local information may beused instead of position information. Such local information is expectedto form a loop of values, where the values rises and/or lowers as afunction of the cardiac cycle and returns to substantially the samevalue at the same phase of every cycle. In some diseased tissue, theloop may close (i.e., return to the same value at the same phase) onlyafter several cycles. The stability of these loops is another indicatorof cardiac health. The form of the loop may be compared betweendifferent locations to assess the relationship between the localinformation values and electrical activation time, mechanical activationand other indicators of the action potential, including the plateaustart and end.

In accordance with a preferred embodiment of the invention, localmechanical activation and/or other local mechanical activity, such asthe end of the contraction, may be determined based on a change in thevelocity direction or in the acceleration direction at a location. Itshould be appreciated that the velocity and acceleration may be referredto as three dimensional vectors in space or as simple one dimensionalvectors. Thus, one map in accordance with a preferred embodiment of theinvention, graphs changes in the velocity and acceleration profile as afunction of the movement of the catheter.

Another type of map in accordance with a preferred embodiment of theinvention, shows the absolute peak-to-peak voltage at each location. Inhealthy tissue the value of this voltage may be one or more orders ofmagnitude higher than in scar tissue, with diseased tissue havingintermediate values. Thus, different types of cardiac tissues may beidentified based on the measured peak-to-peak voltage.

Another type of analysis relates to changes in area at a location. In apreferred embodiment of the invention, the surface of the heart isreconstructed using a star based algorithm, as polygons, preferablytriangles, with each point being a location. The area surrounding alocation is defined as the area in the polygons which include thelocation. One type of map in accordance with a preferred embodiment ofthe present invention shows the changes in the area surrounding thelocation as a function of time. The area generally indicates localcontractile performance. Another type of analysis is determining warpingof the polygons as a function of the cardiac cycle. This analysis can beused to calculate stress and/or strain at the location.

In a preferred embodiment of the invention, maps are compared before andafter a medical procedure to assess its success. In addition, it may bedesirable to compare maps taken at different times and at differentlevels of cardiac activity and demand, for example, before, during andafter exercise. In some patients it may not be practical to performexercise, so a chemical, test, such as using Dobutamine, may be appliedinstead of a physical stress test.

As explained above, maps can be used to determine clinical informationabout the heart. Preferably, maps are constructed and analyzed inpreparation for a therapeutic procedure or in assessing the success of atherapeutic procedure. For example, scar tissue neither reacts to norconducts an electrical signal, while hibernating muscle tissue conductsthe activation signal but does not react to it. A map, as describedabove, can be used to differentiate between these and other types oftissue.

Aneurysms are readily detectable on a geometric map, as bulges duringsystole. Furthermore, potential aneurysms can be detected soon after anAMI (acute myocardial infraction) from local reactions to an activationsignal and local reactions to changes in intracardiac pressure, even ifthey are not visible to the naked eye. Automatic detection may be basedon paradoxical movement, in which an over-stressed portion of the heartexpands (and bulges out) when the heart contracts and contracts when theheart expands.

The maps can be used to improve pumping efficiency of the heart. In anefficiently operating heart, each heart segment has an optimal relationbetween its activation time and the cardiac cycle. Using one of theabove described maps, the relationship between the local activation timeand the cardiac cycle can be determined. Using a finite-element model ofthe heart as a pump, underutilized segments of the heart can bedetermined. The potential for improvement in the heart output can bedetermined from the model and different methods of improving heartfunction, such as described below, can be tested.

A preferred embodiment of the invention provides a solution to mappingwhen heart 20 has a non-constant rate. In one case, the heart ratevaries, however, it is not arrhythmic. In this case, each heart beat maybe treated as one time unit, with an appropriate scaling. Where heartbeat is arrhythmic, either naturally, or by choice (manual pacing),position and other sensed values are binned according to ECG orelectrogram morphology, beat length, activation location, relativeactivation time or other determined cardiac parameters. Thus, aplurality of maps may be constructed, each of which corresponds to onebin. FIG. 11 is a flowchart of a preferred binning method. Localinformation is acquired simultaneously with an associated 12 lead bodysurface ECG. The morphology of the acquired ECG is correlated with aplurality of stored ECG traces. The local information is stored in a binwhich has the highest correlation. Preferably, if the correlation isbelow a predetermined limit, a new bin is created having the acquiredECG as its associated ECG.

It should be appreciated that locally determined characteristics, suchas local electrogram, are associated with a particular segment of heart20, so that local twisting, moving and contractions can be determined.In many prior art systems, a map of the electrical activity of heart 20is not associated with specific segments of heart 20 but with generalfeatures.

A preferred embodiment of the invention utilizes adaptive mechanisms ofthe human heart to change the heart, in particular the distribution ofmuscle mass in the heart.

A general property of muscle tissue, including cardiac muscle, is thatmuscle tissue hypertrophies in reaction to increased stress andatrophies in reaction to reduced stress. According to a preferredembodiment of the invention, the stress and/or workload in the heart areredistributed to affect the distribution of cardiac muscle mass.Preferably, redistribution of stress and/or workload is achieved bychanging the location of pacing in the heart. Muscle tissue that isactivated sooner has a longer plateau, and as a result has a longerworking time. Muscle which is activated later has a greater initialcontractile force (due to its longer initial length caused by the raisein intra-cardiac pressure), but has a shorter plateau and a shorterworking time, which mean lower workload. Thus, workload can beredistributed by changing the pacing location.

It should be noted that increasing the plateau duration of a musclesegment can cause both atrophy and hypertrophy of the muscle segment. Ingeneral, increasing the plateau duration increases the both the amountof work performed by the muscle segment and the force that the muscleexerts. As a result, the muscle segment may atrophy. However, if themuscle is diseased, the exerted force may not be increased. Further,changing the activation time may reduce the effectiveness of the muscle,so that it hypertrophies, even if the plateau duration was increased.Further, it may be desirable to activate a muscle portion early and/orto extend its activation duration so that better perfused muscle willtake over the work of less perfused muscle. Thus, even if thecontractile force exerted by the muscle is increased by the increase inplateau duration, this increase is not sufficient to compensate for theincrease in workload requirement, with the result that the musclehypertrophies. Also, since the extent of ionic currents is usuallydifferent in healthy and diseased hearts, the effect of changing theplateau duration may be different.

Local uncompensated stress is caused by an increase in intra-cardiacpressure before the muscle is activated (to compensate). In healthytissue, this stress results in a small amount of stretching, however, inweakened tissue, the stretching may be considerable and cause damage tothe muscle. Since changing the pacing affects the amount of local stresswhich is not compensated for by muscle contraction, stress can also beredistributed by changing the pacing.

FIG. 12A shows a heart 20′ having a hypertrophied ventricular septum109. The activation of the left ventricle of heart 20′ typically startsfrom a location 108 at the apex of heart 20′, with the result that theactivation times of a location 110 in an external wall 111 issubstantially the same as the activation time of a location 112 inseptum 109. If the initial activation location is moved from location108 to location 112, e.g. by external pacing, septum 109 will be moreefficiently utilized, while wall 111 will be activated later in thesystole, resulting in a shorter plateau duration of wall 111. As aresult, wall 111 will hypertrophy and septum 109 will atrophy, which isa desired result. It should be appreciated, that not all pathologicalchanges in muscle-mass distribution are reversible, especially ifslippage of muscle fibers and/or formation of scar tissue are involved.

Another preferred embodiment of the invention relates to changing theactivation profile of the heart in order to reduce the stress on certainportions of the heart. FIG. 12B shows a heart 20″ having a partiallyinfarcted portion 114. Portion 114 has less muscle mass than other partsof wall 111 and, in addition, may be activated later in the cardiaccycle than optimal. As a result, an aneurysm can be expected to form atportion 114. Pacing at location 116, with or without pacing at location108, both stimulates the existing muscle tissue at portion 114 and,since portion 114 is always contracted when other portions of the leftventricle are contracting, reduces the chances of stretching.

Instead of redistributing stress, other local physiological values canredistributed, for example, a local oxygen requirement. As is wellknown, the local oxygen requirement is directly related to the localworkload. In some diseased hearts, the coronary arteries perfusing afirst portion of the heart are more limited in their oxygenationcapability than the coronary arteries perfusing a second portion of theheart. In a patient suffering from chronic ischemia in the first portionof the heart, it may be advantageous to redistribute the workload sothat the first portion has less workload and the second portion has moreworkload. FIG. 12C shows heart 20″ having a first portion 120 thatsuffers from chronic ischemia and a second portion 122 that is welloxygenated. If the pacing of the left ventricle of heart 20″ is movedfrom its normal location 108 to a location 124, portion 122 takes overpart of the workload of portion 120.

Another type of redistribution relating to perfusion utilizes the factthat the coronary muscle perfuses best during diastole. In a hearthaving long conduction pathways, some portions may have a very latesystole and, as a result, be poorly perfused. In a preferred embodimentof the invention, late activated portions of the heart are paced so thatthey are activated earlier and, as a result, are better perfused.

As can be appreciated, many physiological values can be redistributed ina more optimal manner by correctly pacing the heart. In particular,local physiological values can be kept within a preferred range bytemporal or spatial redistribution. For example, by pacing once from afirst location and once from a second location, the average stress atthe first location can be equalized to the average stress at the secondlocation.

Another aspect of the present invention relates to optimizing a globalparameter of cardiac operation (physiological variable), for example,increasing the cardiac efficiency which ultimately increases the cardiacoutput and may reduce hypertrophy. The amount of work actually performedby a cardiac muscle segment is dependent on its plateau length (which isdependent on its activation time) and on the correct sequencing ofactivation of different muscle segments. In an extreme case, a healthyportion of the heart is not activated at all during the cardiac cycledue to a conduction block. In a preferred embodiment of the invention,the output of the heart is increased by changing the activation profileof the heart to better utilize the existing muscle tissue.

FIG. 12D shows heart 20″ having a substantially inactive muscle segment126 which is closer to natural pacing location 108 of the left ventricleand a healthy muscle segment 130 which is further away from pacinglocation 108. Muscle segment 130 is not called upon to perform as muchwork as it can because of its late activation time, on the other hand,segment 126 cannot perform as much work as it should since it isinfarcted. Pacing the left ventricle from location 128 transfers thedemand from segment 126 to segment 130, which is able to answer thedemand. As a result, the output and efficiency of heart 20″ increase. Ifheart 20″ hypertrophied to compensate for its reduced output, thehypertrophy may be reversed. Other compensatory mechanisms, such asincreased heart rate may also be reversed, resulting in less stress onheart 20″.

It should be appreciated that changing the pacing location also affectsthe utilization of ventricular septum 30. Using a multi-location pacingscheme it is possible to pace at location 128 and simultaneously paceventricular septum 30, so that it is properly utilized.

Other cardiac physiological variables can also be optimized using themethods of the present invention. For example, by changing theactivation profile of the heart, the pressure gradient of the heart canbe matched to the impedance of the circulatory system. For example,hypertrophy is an adaptive mechanism for hardening arteries. Theincrease in size of the left ventricle results in a less pulsile flowwhich more readily enters the hardened arteries. By changing theactivation profile of the heart, the pulse can be made less pulsilewithout hypertrophy. Other variables which may be optimized include, butare not limited to, heart rate, diastolic interval, long axis and/orshort axis shortening, ejection fraction, valvular cross-sectional area,and parameters of the vascular system, such as blood volume andvelocity, blood-vessel cross-sectional area and blood pressure. Itshould be appreciated that such a variable may have a single value or ahave a continually changing value whose profile is to be optimized.

In an additional embodiment of the invention, the activation profile ofthe heart is changed to reduce the maximum intra-cardiac pressure.Although such a reduction typically reduces the heart output, it may belifesaving in case of an aortic or cardiac aneurysm.

Pacing the heart in the above described embodiments of the invention canbe performed in many ways. One pacing method does not require implantinga cardiac pacemaker. Rather, the conduction pathways in the heart aremapped and several of the pathways are disconnected to permanentlychange the activation profile of the heart. Disconnecting the pathwayscan be achieved by surgically removing portions of pathways or byablating those portions, using methods known in the art. Alternatively,new conduction pathways can be formed in the heart, by surgicallyconnecting pathways, by implanting conductive tissues or by implantingelectrical conductors. For example, an electrical lead having a distalend and a proximal end, which are both highly conductive, and which canact as a conduction pathway. Optionally, the lead includes a miniaturecircuitry which charges a capacitor with the plateau voltage from theproximal end and discharges the voltage as an activation signal at thedistal end.

Alternatively, a pacemaker can be implanted. Typically, the AV node isablated and the ventricle is paced as described hereinabove.Alternatively, the AV node is not ablated, the SA node activation signalis sensed and the ventricles are activated artificially before thesignal from the AV node arrives at the ventricles. In some embodimentsof the invention, such as those explained with reference to FIG. 12B,pacing can proceed in parallel both through the natural pathways andthrough the artificial ones, with similar beneficial results.

It should be appreciated that the use of multi-electrode pacemakerswidens the variety of possible activation profiles and enables a betteroptimization. In particular, activation times can be more preciselycontrolled using a multi-electrode pacemaker. Also, the local plateaulength can be better controlled when using multi-location pacing.

Another preferred embodiment of the invention provides a pacemakerutilizing one of the above described pacing methods. In such anembodiment, the pacemaker includes sensors for determining the state ofglobal or local cardiac parameters. For example, the intra-cardiacpressure can be monitored, and if it exceeds a certain amount, thepacing regime is changed to effect a change in the activation profile,which in turn affects the intra-cardiac pressure. In another example,the pacemaker measures the stress in certain segments of the heart, andif the stress in one of the segments exceeds a certain limit, the pacingregime is changed so that the stress in the segment is reduced.

In a preferred embodiment of the invention, the pacemaker determineslocal ischemic conditions, by measuring an injury current. As is knownin the art, when the activity of a segment of muscle tissue is impaired,such as by oxygen starvation, the local voltage at rest is higher thanin normal muscle. This change in voltage can be directly measured usinglocal sensors. Alternatively, isotonic currents caused by the voltagedifference can be measured. Further alternatively, the effect of thevoltage changes on an ECG, which are well known in the art, can beutilized to diagnose an ischemic condition.

In an additional embodiment of the invention, the pacing regime ischanged so that the stress is temporally redistributed between differentsegments of the heart. This type of distribution may be required if ahigh cardiac output is required and most of the heart is chronicallyischemic. By cycling the workload, each portion of the heart gets arecuperation period. A temporal redistribution may also be required ifit is not possible to efficiently activate two portions of the heartsimultaneously, but activation of both is desired so that neither oneatrophies as result of non-use.

In a preferred embodiment of the invention, portions of heart 20 areexercised by changing the pacing temporarily to increase the workload,stress or other local values. After a short time, the pacing is returnedto a previous regime, which demands less of the exercised portions ofheart 20.

There are several ways in which an optimal activation profile and itsoptimal pacing regime can be determined. In one preferred embodiment ofthe invention, a map of the heart is constructed and analyzed todetermine an optimal activation profile. Such determination is usuallyperformed using a model of the heart, such as a finite-element model. Itshould be appreciated that a relatively simple map is sufficient in manycases. For example, an activation-time map is sufficient for determiningsome portions of the heart which are activated too late in the cardiaccycle and are, thus, under utilized. In another example, A map ofthickness changes is sufficient to determine portions of the heart whichare inactive and/or to detect aneurysms.

Additionally or alternatively, an iterative method is used. A firstpacing regime may be determined by analyzing a map or by heuristicmethods. After application of the pacing regime, an optimizationvariable or a distribution of a local variable are measured and thepacing regime changed appropriately. The cycle length of an iterationmay be very short, such as for an optimizing pacemaker. In muscle massredistribution, for example, the determination of the final pacingregime may take longer. First an initial pacing regime is determined fora heart diseased with HCM, after two or three weeks the heart is imagedand the improvement in the condition is determined. Based on themorphological changes in the heart a new pacing regime may bedetermined. This may be changed a number of times.

A preferred embodiment of the invention relates to optimal placement ofpacemaker electrodes. In the past, when a pacemaker is implanted in aheart, the location of the electrodes is determined based on one of thefollowing factors:

(a) the quality and stability of the electrical contact between theelectrodes and the heart;

(b) the existence of artifacts in the electrogram; and

(c) the effect of the electrode placement and activation timing (formulti-electrode pacemakers) on the heart rhythm.

It should be noted, that since pacemaker electrodes are typicallyimplanted using a fluoroscope, the precision of their placement is low.In a preferred embodiment of the invention, pacemaker electrodeplacement and/or the pacing regime of the pacemaker are determined suchthat at least one cardiac parameter or the distribution of localphysiological values is optimized, as described above.

In a further preferred embodiment of the invention, an electrode istest-implanted, or simulated by pacing from a catheter, in each of aplurality of electrode locations and the heart output associated witheach pacing location is measured. After determining the pacing locationwhich yields the highest cardiac output, the electrode is implanted inthat location. Preferably, the electrode is mounted on a positionsensing catheter to aid in repositioning of the electrode. Preferably,the catheter comprises a peelable sheath enclosing the electrodes, wherethe sheath contains at least one position sensor. Further preferably, asteerable catheter is used. Preferably, the operation of the heart isre-evaluated after one or two weeks to determine the effect of thecardiac-adaptation mechanisms on the position of the optimal pacingposition. If necessary, one or more electrodes are moved. Alternativelyor additionally, when a multi-electrode pacemaker is used, the pacinglocation can be changed by activating alternative electrodes.

FIG. 13 shows an implanted pacemaker according to a preferred embodimentof the invention. A control unit 140 electrifies a plurality ofelectrodes 142 implanted in various locations in heart 20″, inaccordance with at least one of the pacing regimes described above.Various local physiological values of the heart can be determined usingelectrodes 142, for example, local activation time and plateau length.Alternatively or additionally, at least one implanted sensor 146 is usedto determine local physiological values, such as perfusion andthickness. Alternatively or additionally, a cardiac physiologicalvariable is measured using a sensor 144. Examples of physiologicalvariables include, the intra-cardiac pressure which may be measuredusing a solid state pressure transducer and the stroke volume, which maybe measured using a flow velocity sensor in the aorta. Other variablesinclude: heart rate, diastolic interval, long and short axis shortening,ejection fraction and valvular cross-section. In addition, vascularvariables may be measured in any particular vessel, for example,bloodvessel cross-section, vascular flow velocity, vascular flow volumeand blood pressure. Any one of these variables can be used to asses thefunctionality of the heart under a new pacing regime.

It should be appreciated that cardiac mapping can be performed both fromthe inside of the heart by inserting a catheter into the heart and fromthe outside of the heart by inserting the catheter into the coronaryveins and arteries. Further, mapping, especially electrical mapping, canbe performed inside the heart muscle, such as by inserting an electrodecarrying needle into the muscle.

Cardiac mapping in accordance with preferred embodiments of theinvention, is preferably performed using the Carto system (forelectrical mapping) and the Noga system (for electromechanical mapping),both available form Biosense (Israel) Ltd., Tirat HaCarmel, Israel. Somepreferred types of mapping catheters are described in a PCT applicationfiled in Israel on Jan. 8, 1997, by applicant “Biosense” and titled“Mapping Catheter”, the disclosure of which is incorporated herein byreference.

It should also be appreciated that once the position of the catheter isknown, external sensors can be used to provide local physiologicalvalues of heart tissue adjacent to the tip of the sensor. For example,if the tip of the catheter caries an ultra-sound marker, an ultrasoundimage including the marker can be used to determine the local wallthickness. Another example is a combination with SPECT (single photonemission tomography). If the catheter incorporates a radioactive markersuitable for SPECT, local functional information can be gleaned from aSPECT image. Yet another example is determining local perfusion fromDoppler-ultrasound images of the coronaries, from nuclear medicineimages or from X-ray or CT angiography and overlaying the perfusion mapon the geometrical map. In general, a map in accordance with the presentinvention may be overlaid on or combined with many types of medicaldata, for example three-dimensional CT data and the like.

One method of aligning an angiogram or a perfusion map with acatheter-acquired map is to acquire both maps substantiallysimultaneously. The image of the catheter in the perfusion map can thenbe used to determine if the catheter is near a perfused tissue ornonperfused tissue. Alternatively or additionally, a plurality ofreference locations are identified in both the catheter-based map andthe perfusion map, so that the two maps can be aligned. The referencelocations can be locations either inside or outside the body and theymay be identified by placing a position-sensing sensor at the locationduring the catheter-based mapping. Preferably, the reference locationsare also identified during the perfusion mapping by using aposition-sensitive sensor, so that the frames of reference for the twomaps can be automatically aligned, for example, using the referencecatheter as described above. Alternatively or additionally, anappropriate type of radio-opaque or radiative marker is placed on thebody so that it is visible during the perfusion mapping. Alternatively,the reference locations are identified from anatomical or functionaldetails in the two maps.

It should be appreciated that a two dimensional angiogram can bealigned, in a clinically useful manner, with a two-dimensionalprojection of a map of the heart. The appropriate projection directioncan be determined from the relative positions of the patient and theangiographic system during the angiography. Preferably, a bi-planeangiogram is aligned with two two-dimensional projections of a map ofthe heart, alternatively, other types of angiograms or perfusion mapsare used. Alignment may be automatic, using fiduciary marks or referencelocations as described above. Alternatively, manual alignment oranalysis is performed.

It should be appreciated that a catheter can be positioned in almost anypart of the body via the vascular system and via body orifices. Inaddition, a positioning sensing catheter can be surgically inserted inany portion of the body, for example, inserting the catheter into theabdomen or into the thigh. Thus, the above described mapping and pacing(stimulating) methods and apparatus can-also be applied to mapping andstimulating atrophied and injured muscles, mapping the bowels andmapping the electrical and chemical activity of the brain.

The present invention has been described in a plurality of preferredembodiments, each of which has been separately described. It should beappreciated that the present invention contemplates combining variousaspects of different embodiments, for example, various types of mappingsand various types of pacing may be combined in accordance with preferredembodiments of the invention. Further, many different types of mapablelocal physiological variables have been described. In various preferredembodiments of the invention, any number of these variables may bemapped and their coupling analyzed to yield information about theactivity of a heart. The scope of the invention also includes apacemaker designed to or programmed to perform any of the abovedescribed pacing regimes. Further, the scope of the present inventionalso encompasses the act of programming a pacemaker to perform any ofthe above described pacing regimes and the act of modifying pulseparameters in accordance with any embodiment of the present invention.Also, the scope of the invention should be construed to includeanalyzing such maps, as described herein and apparatus, such as acomputer workstation with software, for performing such analyses. Inaddition the scope of the invention should be construed to includeapparatus for acquiring maps as described herein, and in particularsoftware suitable for converting individual local positions, sensedphysiological values and electrical activity into such maps. Also suchapparatus preferably displays such maps to an operator, either as a snapshot or as a dynamic map.

Another aspect of the present invention relates to computer aideddiagnosis. A library of maps representing different types ofpathologies, from many patients may be stored on a computer. Since themaps are typically acquired using a computerized system, inputting themaps is easy. When a patient is diagnosed, the diagnosis is stored alongwith the map, as well as any additional information, such as history,development of the disease, effects of various drugs (with maps to showthese effects), effect of new pacing regimes and the like. When a newmap is made, this map may be correlated with the maps in the library tomore easily diagnose the patient. Maps may be correlated usinganatomical landmarks, fiduciary marks inputted by the user, orgeometrical alignment. In addition a map may be correlated with aprevious map of the same patient to asses the success of a treatment. Ina preferred embodiment of the invention, the computer system include anexpert system which helps with the diagnosis and/or suggests anappropriate treatment. It should be appreciated, that even though eachperson may have a different anatomy and different cardiac disorders,there will be many similarities between maps of different people havingsimilar disorders, such as ischemia due to the blockage of a particularcoronary artery.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has thus far been described. Rather thescope of the present invention is limited only by the claims whichfollow.

1. A method for mapping a heart comprising the steps of: inserting amapping catheter, having a tip and an ultrasonic position sensor locatedat the tip, into the heart; inserting at least one reference catheterhaving an ultrasonic position sensor into the heart; placing the tip ofthe mapping catheter on a surface of the heart at a plurality of pointsin time of a cardiac cycle; determining the position of the mappingcatheter relative to the at least one reference catheter using theultrasonic position sensors by making a geometric snapshot of the heartduring each point in time of the cardiac cycle; and mapping the surfaceof the heart with the mapping catheter and making a map comprised ofeach geometric snapshot.
 2. The method according to claim 1, furthercomprising mapping electrical activity of a portion of the heart with atleast one electrode mounted at the tip of the mapping catheter.
 3. Themethod according to claim 2, further comprising measuring impedance ofthe portion of the heart.
 4. The method according to claim 2, furthercomprising measuring mechanical information of the portion of the heart.5. The method according to claim 4, further comprising measuringmovement of the portion of the heart.
 6. The method according to claim1, further comprising performing a therapeutic procedure on a portion ofthe heart.
 7. The method according to claim 6, further comprisingperforming an ablation procedure on the portion of the heart.
 8. Amethod for mapping a heart comprising the steps of: inserting a mappingcatheter, having a tip and an ultrasonic position sensor located at thetip, into the heart; inserting at least one reference catheter having anultrasonic position sensor outside of the heart; placing the tip of themapping catheter on a surface of the heart at a plurality of points intime of a cardiac cycle; determining the position of the mappingcatheter relative to the at least one reference catheter using theultrasonic position sensors by making a geometric snapshot of the heartduring each point in time of the cardiac cycle; and mapping the surfaceof the heart with the mapping catheter and making a map comprised ofeach geometric snapshot.
 9. The method according to claim 8, furthercomprising mapping electrical activity of a portion of the heart with atleast one electrode mounted at the tip of the mapping catheter.
 10. Themethod according to claim 9, further comprising measuring impedance ofthe portion of the heart.
 11. The method according to claim 9, furthercomprising measuring mechanical information of the portion of the heart.12. The method according to claim 11, further comprising measuringmovement of the portion of the heart.
 13. The method according to claim8, further comprising performing a therapeutic procedure on a portion ofthe heart.
 14. The method according to claim 13, further comprisingperforming an ablation procedure on the portion of the heart.
 15. Amethod for mapping a heart comprising the steps of: (a) inserting amapping catheter, having a tip and an ultrasonic position sensor locatedat the tip, into the heart; (b) inserting at least one referencecatheter having an ultrasonic position sensor into the heart; (c)bringing the tip of the mapping catheter into contact with a wall of theheart at a location at a point in time of a cardiac cycle; (d)determining a position of the tip of the mapping catheter at thelocation using the ultrasonic position sensors and making a geometricsnapshot of the wall of the heart; (e) moving the tip of the mappingcatheter to a second location at another point in time of the cardiaccycle and making a second geometric snapshot of the wall of the heart;and (f) making a map of the wall of the heart based on the geometricsnapshots by repeating steps (d)–(e).
 16. The method according to claim15, further comprising mapping electrical activity of a surface of theheart with at least one electrode mounted at the tip of the mappingcatheter.
 17. The method according to claim 16, further comprisingmeasuring impedance of the surface of the heart.
 18. The methodaccording to claim 15, further comprising performing a therapeuticprocedure on a surface of the heart.
 19. The method according to claim18, further comprising performing an ablation procedure on the surfaceof the heart.
 20. The method according to claim 15, further comprisingmeasuring mechanical information of a surface of the heart.
 21. Themethod according to claim 20, further comprising measuring movement ofthe surface of the heart.
 22. A method for mapping a heart comprisingthe steps of: (a) inserting a mapping catheter, having a tip and anultrasonic position sensor located at the tip, into the heart; (b)inserting at least one reference catheter having an ultrasonic positionsensor outside of the heart; (c) bringing the tip of the mappingcatheter into contact with a wall of the heart at a location at a pointin time of a cardiac cycle; (d) determining a position of the tip of themapping catheter at the location using the ultrasonic position sensorsand making a geometric snapshot of the wall of the heart; (e) moving thetip of the mapping catheter to a second location at another point intime of the cardiac cycle and making a second geometric snapshot of thewall of the heart; and (f) making a map of the wall of the heart basedon the geometric snapshots by repeating steps (d)–(e).
 23. The methodaccording to claim 22, further comprising mapping electrical activity ofa surface of the heart with at least one electrode mounted at the tip ofthe mapping catheter.
 24. The method according to claim 23, furthercomprising measuring impedance of the surface of the heart.
 25. Themethod according to claim 22, further comprising performing atherapeutic procedure on a surface of the heart.
 26. The methodaccording to claim 25, further comprising performing an ablationprocedure on the surface of the heart.
 27. The method according to claim22, further comprising measuring mechanical information of a surface ofthe heart.
 28. The method according to claim 27, further comprisingmeasuring movement of the surface of the heart.